Feeding (eating) is a behavior essential for animals to survive. Obesity is considered to be a result of failure to control or balance feeding and energy consumption in our current society in the age of satiation. Since the obesity is a risk factor for lifestyle diseases and various other diseases, social interest in it has been increasing. Although basic therapies to improve the balance between feeding and energy consumption, such as diet therapy and exercise therapy, have become available, the number of patients and candidates for obesity is currently increasing. Recently, pharmaceutical agents for suppressing nutritional absorption in peripheral tissues and pharmaceutical agents for decreasing the amount of feeding by acting on the central nervous system have been developed; however, development of effective and safe pharmaceutical agents for suppressing the amount of feeding as agents to treat obesity is desired.
It has been gradually revealed that feeding behavior is controlled by a cycle with a direction from the cerebral central nerve and a feedback from the peripheral tissue, whereby a further direction is sent from the central nervous system. Thus, research focusing on the feeding-controlling mechanism in the brain, which plays a major role, has been flourishing. By research using an animal in which a specific region of the brain is destroyed and functional analyses using neuropeptides or neurotransmitters, it has been gradually revealed that a hypothalamus region plays an important role in the feeding behavior. Further, a number of neurotransmitters, neuropeptides and receptors for them are expressed in the hypothalamus and thus their correlation with feeding behavior has been shown. For example, there have been reported that neuropeptide Y, agouti gene-related peptide and the like which are present in the arcuate nucleus of the hypothalamus are involved in feeding-stimulation and that melanocortin which is present in the same region and corticotropin-releasing hormone and thyrotropin-releasing hormone which are released from the paraventricular nucleus of the hypothalamus are involved in feeding-suppression (non-patent reference 1). However, as to the complicated nervous network to control feeding, much remains unrevealed and new findings regarding novel neurotransmitters and their locations are still appearing.
Physiologically active substances which are involved in controlling feeding behavior, such as neurotransmitters and neuropeptides, exhibit their function via specific receptors present in the cell membrane. Of these receptors, receptors which have a structure to penetrate the cell membrane 7 times and are coupled with the G protein trimer in the cells are particularly classified as G-protein-coupled receptors (GPCRs). Upon binding with specific ligands, the GPCRs transmit signals into the cells to activate or suppress the cells and thus play an important role in expressing functions in various organs. Therefore, agonists which activate GPCRs and antagonists which suppress GPCRs have been used as medicines. Of receptors classified into GPCRs, many for which no specific ligand has been identified are known and called orphan GPCRs. The orphan GPCRs have a potential to become a target for novel therapeutic agents, and thus identification of their ligands and research on substances to activate or suppress their function have been in progress. It is extremely important in developing new medicines to elucidate functions of the receptors and their ligands by administering the identified ligands or substances to the body.
In recent years, enrichment of the genetic sequence information makes it possible to predict and identify an unknown peptide or protein as a novel GPCR ligand by deducing its homology and regularity based on sequences of known proteins or peptides. Relaxin, a member of the insulin/relaxin family, is a secretory hormone produced by the corpus luteum or the placenta and has long been known to have functions involved in the maintenance of pregnancy and the delivery. As another function, for example, stimulation of water intake by relaxin-2 intravenously administered in rats has been reported (non-patent reference No. 2); however, correlation between relaxin and feeding behavior has not been known. A protein encoded by a DNA sequence which is newly identified by a gene sequence database based on the base sequence of DNA encoding relaxin is a polypeptide called relaxin-3/INSL7 (patent reference No. 1). Relaxin-3 thus found has been reported to activate cells with an increase in intracellular cyclic AMP (cAMP) of THP-1 cells of the immune system (patent reference No. 2, non-patent reference No. 3). It has later been suggested that relaxin-3, along with relaxin 2, is one of ligands which bind LGR7, a GPCR (non-patent reference No. 4). LGR7 is expressed in the brain and peripheral tissues and has been so far suggested to be involved in development of reproductive organs, pregnancy, and delivery; however, its correlation with feeding has not clearly been understood.
Recently it has been reported that a ligand for GPCRs for which no ligand in the body has been identified, i.e., a receptor called SALPR (GPCR135) and a receptor called GPR100 (hGPCR11, GPCR142), is relaxin-3 (non-patent references Nos. 5 and 6; patent reference No. 3). Further, patent references Nos. 4 to 7 also include descriptions related to these receptors. SALPR is known to locate in the brain (non-patent reference No. 7) and in particular reported to locate in the paraventricular nucleus and the supraoptic nucleus of the hypothalamus (patent reference No. 3; non-patent reference No. 6). On the other hand, GPR100 has been reported to be a receptor which is systemically expressed (non-patent references Nos. 8 and 9); however, its function remains unknown.
On the other hand, relaxin-3 has been reported to be present in the area called the pons in the brain (non-patent reference No. 6) and it has been thought that relaxin-3 may exhibit some functions in the central nervous system as an intracerebral peptide; however, there has been no report on whether relaxin-3 controls feeding or whether relaxin-3 is involved in body weight control. Further, whether relaxin-3 is related to obesity has also not been known.    Patent reference No. 1: WO 01/068862    Patent reference No. 2: Japanese Patent Laid-open No. 2002-345468    Patent reference No. 3: WO 2004/082598    Patent reference No. 4: WO 00/24891    Patent reference No. 5: WO 01/48189    Patent reference No. 6: WO 02/31111    Patent reference No. 7: WO 02/61087    Non-patent reference No. 1: Spiegelman et al., Cell, 104, p. 541-543, 2001    Non-patent reference No. 2: Sinnayah et al., Endocrinology, 140, p. 5082-5086, 1999    Non-patent reference No. 3: Bathgate et al., J. Biol. Chem., 277, p. 1148-1157, 2002    Non-patent reference No. 4: Sudo et al., J. Biol. Chem., 278, p. 7855-7862, 2003    Non-patent reference No. 5: Takeda et al., FEBS Letter, 520, p. 97-101, 2002    Non-patent reference No. 6: Liu et al., J. Biol. Chem., 278, p. 50754-50764, 2003    Non-patent reference No. 7: Matsumoto et al., Gene, 248, p. 183-189, 2000    Non-patent reference No. 8: Liu et al., J. Biol. Chem., 278, p. 50765-50770, 2003    Non-patent reference No. 9: Boels et al., Br. J. Pharmacol., 140, p. 932-938, 2003